Anti-PDCD1 monoclonal antibody, clone K227

BACKGROUND: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology. METHODS: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort. RESULTS: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2-1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4-1.9; p = NS). CONCLUSIONS: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.

Although human leukocyte antigen (HLA)-B27 gene is the major susceptible gene associated with ankylosing spondylitis (AS), it has been recognized that non-HLA-B27 genes also play key roles in the development of AS. The purpose of this study is to investigate whether a single nucleotide polymorphism (SNP) in the exon region of the programmed cell death 1 (PDCD-1) gene is associated with the susceptibility or the thoracolumbar kyphosis severity of AS in a Chinese Han population. A total of 255 AS patients between January 2008 and October 2012 were recruited in this study. Two hundred and three healthy patients were recruited as normal controls. According to the severity of thoracolumbar kyphosis, the AS patients were further divided into group A (patients with kyphosis < 70A degrees, n = 135) and group B (patients with kyphosis a parts per thousand yen70A degrees, n = 120). One exon polymorphism, rs2227982 (C/T) of PDCD-1 gene, was selected for analysis. Genotyping was performed by TaqMan probe assays in all the subjects. There were significant differences of genotype distributions of rs2227982 between AS patients and normal controls. The frequency of the T allele was significantly higher in AS patients when compared with normal controls. The frequency of the T allele in group B was significantly higher than that in group A. Carriage of the TT genotype increased the risk of severe thoracolumbar kyphosis 1.9-fold in AS patients. Our study confirms a significant association between the SNP rs2227982 of PDCD-1 gene and the susceptibility of AS in a Chinese Han population. Moreover, the TT genotype is suggested to be associated with the severity of thoracolumbar kyphosis secondary to AS.